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1.
Nat Commun ; 11(1): 4997, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020472

RESUMO

Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Interleucina-33/metabolismo , Animais , Neoplasias Encefálicas/mortalidade , Carcinogênese , Núcleo Celular/metabolismo , Citocinas/metabolismo , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/mortalidade , Humanos , Inflamação , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos SCID , Microglia , Análise de Sobrevida , Linfócitos T/metabolismo , Linfócitos T/patologia , Microambiente Tumoral/imunologia
2.
Nat Commun ; 11(1): 5084, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033253

RESUMO

Identifying factors underlying resistance to immune checkpoint therapy (ICT) is still challenging. Most cancer patients do not respond to ICT and the availability of the predictive biomarkers is limited. Here, we re-analyze a publicly available single-cell RNA sequencing (scRNA-seq) dataset of melanoma samples of patients subjected to ICT and identify a subset of macrophages overexpressing TREM2 and a subset of gammadelta T cells that are both overrepresented in the non-responding tumors. In addition, the percentage of a B cell subset is significantly lower in the non-responders. The presence of these immune cell subtypes is corroborated in other publicly available scRNA-seq datasets. The analyses of bulk RNA-seq datasets of the melanoma samples identify and validate a signature - ImmuneCells.Sig - enriched with the genes characteristic of the above immune cell subsets to predict response to immunotherapy. ImmuneCells.Sig could represent a valuable tool for clinical decision making in patients receiving immunotherapy.


Assuntos
Perfilação da Expressão Gênica , Imunoterapia , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores Imunológicos/metabolismo , Linfócitos T/metabolismo , Área Sob a Curva , Linfócitos B/metabolismo , Biomarcadores Tumorais/metabolismo , Humanos , Macrófagos/patologia , Melanoma/genética , Melanoma/patologia , Reprodutibilidade dos Testes
3.
PLoS Pathog ; 16(9): e1008879, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32997728

RESUMO

The Human T-cell leukemia virus type 1 (HTLV-1) orf I-encoded accessory protein p8 is cleaved from its precursor p12, and both proteins contribute to viral persistence. p8 induces cellular protrusions, which are thought to facilitate transfer of p8 to target cells and virus transmission. Host factors interacting with p8 and mediating p8 transfer are unknown. Here, we report that vasodilator-stimulated phosphoprotein (VASP), which promotes actin filament elongation, is a novel interaction partner of p8 and important for p8 and HTLV-1 Gag cell-to-cell transfer. VASP contains an Ena/VASP homology 1 (EVH1) domain that targets the protein to focal adhesions. Bioinformatics identified a short stretch in p8 (amino acids (aa) 24-45) which may mediate interactions with the EVH1 domain of VASP. Co-immunoprecipitations confirmed interactions of VASP:p8 in 293T, Jurkat and HTLV-1-infected MT-2 cells. Co-precipitation of VASP:p8 could be significantly blocked by peptides mimicking aa 26-37 of p8. Mutational studies revealed that the EVH1-domain of VASP is necessary, but not sufficient for the interaction with p8. Further, deletion of the VASP G- and F-actin binding domains significantly diminished co-precipitation of p8. Imaging identified areas of partial co-localization of VASP with p8 at the plasma membrane and in protrusive structures, which was confirmed by proximity ligation assays. Co-culture experiments revealed that p8 is transferred between Jurkat T-cells via VASP-containing conduits. Imaging and flow cytometry revealed that repression of both endogenous and overexpressed VASP by RNA interference or by CRISPR/Cas9 reduced p8 transfer to the cell surface and to target Jurkat T-cells. Stable repression of VASP by RNA interference in chronically infected MT-2 cells impaired both p8 and HTLV-1 Gag transfer to target Jurkat T-cells, while virus release was unaffected. Thus, we identified VASP as a novel interaction partner of p8, which is important for transfer of HTLV-1 p8 and Gag to target T-cells.


Assuntos
Moléculas de Adesão Celular , Adesões Focais , Produtos do Gene gag , Vírus Linfotrópico T Tipo 1 Humano , Proteínas dos Microfilamentos , Fosfoproteínas , Linfócitos T , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Adesões Focais/química , Adesões Focais/genética , Adesões Focais/metabolismo , Adesões Focais/virologia , Produtos do Gene gag/química , Produtos do Gene gag/genética , Produtos do Gene gag/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/química , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Células Jurkat , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Domínios Proteicos , Linfócitos T/química , Linfócitos T/metabolismo , Linfócitos T/virologia
4.
Anticancer Res ; 40(9): 5221-5227, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878810

RESUMO

BACKGROUND/AIM: Bladder cancer (BLCA, urothelial bladder cancer) is one of the most common malignancies with increasing incidence and mortality worldwide. Poor diagnosis and the limitation of treatment is still an unmet need in clinical practice. γδ T-Cells have been paid increasing attention because of their potent cytotoxicity against tumors. Herein, we investigated the cytolytic effect of γδ T-cells in combination with the chemotherapeutic drug, carboplatin, against BLCA cells. MATERIALS AND METHODS: The standard protocol for the induction and expansion of peripheral blood mononuclear cell-derived γδ T-cells was a zoledronic acid/interleukin-2-based medium system for 2 weeks. The cytotoxicity of γδ T-cells with and without carboplatin against BLCA cells was examined. RESULTS: After incubation, T-cell receptor-positive γδ T-cells showed a natural killer cell-like phenotypic characteristic and dose-dependently increased cytotoxicity against BLCA cells. Interestingly, we found that in advanced BLCA cells, which were more resistant to carboplatin, the cell viability was significantly (p<0.05) reduced in the presence of γδ T-cells. CONCLUSION: Our findings showed that γδ T-cell therapy has potent benefit in cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Carboplatina/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Neoplasias da Bexiga Urinária/patologia
5.
Anticancer Res ; 40(9): 5309-5311, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878822

RESUMO

BACKGROUND/AIM: Experimental studies have shown that celecoxib is related to the downregulation of Tregs and an increase in the therapeutic efficacy of PD-1 inhibitors; however, such effect has not been shown in human cancers. Our report confirmed the synergistic effect of celecoxib with a PD-1 inhibitor. CASE REPORT: A 57-year-old male with advanced pulmonary adenocarcinoma was treated with nivolumab monotherapy as 5th line sequential treatment. Although the patient experienced tumor remission, regrowth of the primary tumor was observed and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend of carcinoma embryonic antigen. CONCLUSION: This is the report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Celecoxib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Sinergismo Farmacológico , Receptores ErbB/genética , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Radiografia Torácica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
6.
Nat Commun ; 11(1): 4367, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868763

RESUMO

Invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT), and γδ T cells are innate T cells that acquire memory phenotype in the thymus and share similar biological characteristics. However, how their effector differentiation is developmentally regulated is still unclear. Here, we identify analogous effector subsets of these three innate T cell types in the thymus that share transcriptional profiles. Using single-cell RNA sequencing, we show that iNKT, MAIT and γδ T cells mature via shared, branched differentiation rather than linear maturation or TCR-mediated instruction. Simultaneous TCR clonotyping analysis reveals that thymic maturation of all three types is accompanied by clonal selection and expansion. Analyses of mice deficient of TBET, GATA3 or RORγt and additional in vivo experiments corroborate the predicted differentiation paths, while human innate T cells from liver samples display similar features. Collectively, our data indicate that innate T cells share effector differentiation processes in the thymus.


Assuntos
Diferenciação Celular , Imunidade Inata , Linfócitos T/metabolismo , Timo/imunologia , Animais , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Humanos , Fígado/citologia , Fígado/imunologia , Ativação Linfocitária , Camundongos , Células T Invariáveis Associadas à Mucosa/metabolismo , Células T Matadoras Naturais/metabolismo , Análise de Sequência de RNA , Análise de Célula Única , Células Th17/metabolismo , Timo/citologia
7.
N Engl J Med ; 383(12): 1149-1155, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32937047

RESUMO

Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.).


Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Glicoproteínas de Membrana/antagonistas & inibidores , Plasmócitos/efeitos dos fármacos , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Creatinina/sangue , Creatinina/urina , Regulação para Baixo , Feminino , Humanos , Interferon Tipo I/antagonistas & inibidores , Quimioterapia de Manutenção , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteinúria , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
8.
Eur Rev Med Pharmacol Sci ; 24(17): 9182-9187, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32965012

RESUMO

COVID-19 pandemic has underlined that unknown viral infections, which jump from animals to humans, can be extremely dangerous. In case of new viruses as SARS-CoV2, available drugs can fail to contrast the virus aggressiveness leading patients to death. Long time is necessary to create a vaccine, but immediate solutions are necessary to stop the mortality COVID-19 related. We have learned that the immune-system is the key to reduce the severity of COVID-19 and, through its modulation, it has been possible saving people's life. In this short communication, we discuss the use of nutraceuticals to modulate and stimulate the immune answer for reducing the severity of COVID-19 symptoms. The nutraceuticals are safe and can be administered to all ages. In addition, combination of natural anti-viral elements and immune-stimulating molecules already successfully tested against others upper-respiratory tract infections-could be efficient against SARS-CoV2. We believe that these natural molecules could really be a valid ally against COVID-19, especially in this moment in which a SARS-CoV2 vaccine is still not available.


Assuntos
Infecções por Coronavirus/terapia , Suplementos Nutricionais , Pneumonia Viral/terapia , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Lactobacillus/fisiologia , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Selênio/farmacologia , Selênio/uso terapêutico , Índice de Gravidade de Doença , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Replicação Viral/efeitos dos fármacos
9.
Adv Exp Med Biol ; 1255: 29-50, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949388

RESUMO

T cells recognize peptides bound to major histocompatibility complex (MHC) class I and class II molecules at the cell surface. This recognition is accomplished by the expression of T cell receptors (TCR) which are required to be diverse and adaptable in order to accommodate the various and vast number of antigens presented on the MHCs. Thus, determining TCR repertoires of effector T cells is necessary to understand the immunological process in responding to cancer progression, infection, and autoimmune development. Furthermore, understanding the TCR repertoires will provide a solid framework to predict and test the antigen which is more critical in autoimmunity. However, it has been a technical challenge to sequence the TCRs and provide a conceptual context in correlation to the vast number of TCR repertoires in the immunological system. The exploding field of single-cell sequencing has changed how the repertoires are being investigated and analyzed. In this review, we focus on the biology of TCRs, TCR signaling and its implication in autoimmunity. We discuss important methods in bulk sequencing of many cells. Lastly, we explore the most pertinent platforms in single-cell sequencing and its application in autoimmunity.


Assuntos
Receptores de Antígenos de Linfócitos T/genética , Análise de Sequência , Análise de Célula Única , Animais , Autoimunidade/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
10.
Nucleic Acids Res ; 48(15): 8724-8739, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32735645

RESUMO

T cell activation is a well-established model for studying cellular responses to exogenous stimulation. Motivated by our previous finding that intron retention (IR) could lead to transcript instability, in this study, we performed BruChase-Seq to experimentally monitor the expression dynamics of nascent transcripts in resting and activated CD4+ T cells. Computational modeling was then applied to quantify the stability of spliced and intron-retained transcripts on a genome-wide scale. Beyond substantiating that intron-retained transcripts were considerably less stable than spliced transcripts, we found a global stabilization of spliced mRNAs upon T cell activation, although the stability of intron-retained transcripts remained relatively constant. In addition, we identified that La-related protein 4 (LARP4), an RNA-binding protein (RBP) known to enhance mRNA stability, was involved in T cell activation-dependent mRNA stabilization. Knocking out Larp4 in mice destabilized Nfκb1 mRNAs and reduced secretion of interleukin-2 (IL2) and interferon-gamma (IFNγ), two factors critical for T cell proliferation and function. We propose that coordination between splicing regulation and mRNA stability may provide a novel paradigm to control spatiotemporal gene expression during T cell activation.


Assuntos
Interferon gama/genética , Interleucina-2/genética , Proteínas/genética , Estabilidade de RNA/genética , Transcriptoma/genética , Processamento Alternativo/genética , Animais , Humanos , Íntrons/genética , Ativação Linfocitária/genética , Camundongos , NF-kappa B/genética , Ligação Proteica/genética , RNA Mensageiro/genética , Linfócitos T/metabolismo
11.
Nat Commun ; 11(1): 4034, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788576

RESUMO

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with severe platelet abnormalities and complex immunodeficiency. Although clinical gene therapy approaches using lentiviral vectors have produced encouraging results, full immune and platelet reconstitution is not always achieved. Here we show that a CRISPR/Cas9-based genome editing strategy allows the precise correction of WAS mutations in up to 60% of human hematopoietic stem and progenitor cells (HSPCs), without impairing cell viability and differentiation potential. Delivery of the editing reagents to WAS HSPCs led to full rescue of WASp expression and correction of functional defects in myeloid and lymphoid cells. Primary and secondary transplantation of corrected WAS HSPCs into immunodeficient mice showed persistence of edited cells for up to 26 weeks and efficient targeting of long-term repopulating stem cells. Finally, no major genotoxicity was associated with the gene editing process, paving the way for an alternative, yet highly efficient and safe therapy.


Assuntos
Edição de Genes , Terapia Genética , Células-Tronco Hematopoéticas/metabolismo , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/terapia , Animais , Plaquetas/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem da Célula , Códon/genética , Feminino , Loci Gênicos , Células HEK293 , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Testes de Mutagenicidade , Células Mieloides/metabolismo , Linfócitos T/metabolismo , Síndrome de Wiskott-Aldrich/patologia , Proteína da Síndrome de Wiskott-Aldrich/genética
12.
PLoS One ; 15(8): e0238070, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853219

RESUMO

Factors regulating self-antigen directed immune-responses in autoimmunity are poorly understood. Signal regulatory protein gamma (SIRPγ) is a human T-cell specific protein with genetic variants associated with type 1 diabetes (T1D). SIRPγ's function in the immune system remains unclear. We show that T1D and relapsing remitting multiple sclerosis (RRMS) subjects have significantly greater frequency of rs2281808 T genetic variant, that correlates with reduced SIRPγ-expression in T-cells. Importantly, reduced SIRPγ-expression in RRMS and T1D subjects was not restricted to T variant, suggesting SIRPγ-expression is also regulated by disease specific factors in autoimmunity. Interestingly, increased frequencies of SIRPγlow T-cells in RRMS and T1D positively correlated with proinflammatory molecules from T-cells. Finally, we show that SIRPγlow T-cells have enhanced pathogenecity in vivo in a GVHD model. These findings suggest that decreased-SIRPγ expression, either determined by genetic variants or through peripherally acquired processes, may have a mechanistic link to autoimmunity through induction of hyperactive T-cells.


Assuntos
Antígenos de Diferenciação/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Regulação da Expressão Gênica , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Receptores Imunológicos/genética , Linfócitos T/metabolismo , Adulto , Alelos , Animais , Autoimunidade , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Recidiva , Linfócitos T/imunologia , Adulto Jovem
13.
Nat Commun ; 11(1): 4166, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820173

RESUMO

T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.


Assuntos
Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica/imunologia , Humanos , Ativação Linfocitária/imunologia , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo
14.
Sci Rep ; 10(1): 14179, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843695

RESUMO

A novel coronavirus (SARS-CoV-2) emerged from China in late 2019 and rapidly spread across the globe, infecting millions of people and generating societal disruption on a level not seen since the 1918 influenza pandemic. A safe and effective vaccine is desperately needed to prevent the continued spread of SARS-CoV-2; yet, rational vaccine design efforts are currently hampered by the lack of knowledge regarding viral epitopes targeted during an immune response, and the need for more in-depth knowledge on betacoronavirus immunology. To that end, we developed a computational workflow using a series of open-source algorithms and webtools to analyze the proteome of SARS-CoV-2 and identify putative T cell and B cell epitopes. Utilizing a set of stringent selection criteria to filter peptide epitopes, we identified 41 T cell epitopes (5 HLA class I, 36 HLA class II) and 6 B cell epitopes that could serve as promising targets for peptide-based vaccine development against this emerging global pathogen. To our knowledge, this is the first study to comprehensively analyze all 10 (structural, non-structural and accessory) proteins from SARS-CoV-2 using predictive algorithms to identify potential targets for vaccine development.


Assuntos
Betacoronavirus/imunologia , Biologia Computacional , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Interações Hospedeiro-Patógeno/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Virais/imunologia , Sequência de Aminoácidos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Betacoronavirus/classificação , Betacoronavirus/genética , Betacoronavirus/metabolismo , Biologia Computacional/métodos , Infecções por Coronavirus/metabolismo , Epitopos de Linfócito B/química , Epitopos de Linfócito T/química , Genoma Viral , Genômica/métodos , Humanos , Modelos Moleculares , Pandemias , Peptídeos/química , Peptídeos/imunologia , Filogenia , Pneumonia Viral/metabolismo , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vacinas de Subunidades/imunologia , Proteínas Virais/química , Vacinas Virais/imunologia
15.
PLoS One ; 15(8): e0235753, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745080

RESUMO

CD154 plays a major role in the pathogenesis of several autoimmune and inflammatory diseases. In addition to CD40, soluble CD154 (sCD154) binds to other receptors namely αIIbß3, αMß2, α5ß1 and αvß3 integrins. We have previously reported that binding of sCD154 to α5ß1 integrin expressed on several human T cell lines is capable of inhibiting Fas-induced cell death. In the current study, we show that such effect of the sCD154/α5ß1 interaction is not restricted to the cell death response induced by Fas but could also be exhibited toward other death signals such as TRAIL and TNF- α. We also demonstrate that sCD154 is capable of inhibiting Fas-mediated death of human activated T cells, more importantly of CD4+ than CD8+ T ones. Our data also show that membrane-bound CD154 and α5ß1 integrin expressed on the surface of distinct cells failed to influence cell death responses. However, when membrane-bound CD154 and α5ß1 are expressed on the surface of same cell, their interaction was capable of down regulating cell death. CD154 was shown to co-localize with the α5ß1 integrin on the surface of these cells. These data strongly suggest a cis-type of interaction between CD154 and α5ß1 when both are expressed on the same cell surface, rather than a trans-interaction which usually implicates the ligand and its receptor each expressed on the surface of a distinct cell. Taken together, these findings add to the list of roles through which CD154 is contributing to the pathogenesis of autoimmune-inflammatory diseases, i.e. by protecting T cells from death and enhancing their survival.


Assuntos
Ligante de CD40/metabolismo , Integrina alfa5beta1/metabolismo , Linfócitos T/citologia , Ligante de CD40/análise , Morte Celular , Células HEK293 , Humanos , Inflamação/metabolismo , Integrina alfa5beta1/análise , Células Jurkat , Mapas de Interação de Proteínas , Linfócitos T/metabolismo
16.
Gene ; 760: 145021, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32763489

RESUMO

Human B cell activating factor (TNFSF13B, BAFF) is a tumor necrosis factor superfamily member. Binding its unique receptor (TNFRSF13C, BAFF-R) mediates gene expression and cell survival in B cells via activation of NFκB pathway. Furthermore, there is data indicating a role in T cell function. A functionally inhibitory isoform (ΔBAFF) resulting from the deletion of exon 3 in the TNFSF13B pre-RNA has already been reported. However, data on the complexity of post-transcriptional regulation is scarce. Here, we report molecular cloning of nine TNFSF13B transcript variants resulting from alternative splicing of the TNFSF13B pre-mRNA including BAFFX1. This variant is characterized by a partial retention of intron 3 of the TNFSF13B gene causing the appearance of a premature stop codon. We demonstrate the expression of the corresponding BAFFX1 protein in Jurkat T cells, in ex vivo human immune cells and in human tonsillar tissue. Thereby we contribute to the understanding of TNFSF13B gene regulation and reveal that BAFF is regulated through a post-transcriptional mechanism to a greater extent than reported to date.


Assuntos
Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Processamento Alternativo/genética , Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Éxons , Expressão Gênica , Humanos , NF-kappa B/metabolismo , Isoformas de Proteínas/genética , Precursores de RNA/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/genética
17.
Zool Res ; 41(5): 503-516, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32772513

RESUMO

As of June 2020, Coronavirus Disease 2019 (COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years, making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To examine the effect of age on death, we established a SARS-CoV-2 infection model in Chinese rhesus macaques ( Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b + and CD8 + cells in lungs at one-week post infection (wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b + cells, and persistent infiltration of CD8 + cells in the lungs at 2 wpi. In addition, peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.


Assuntos
Envelhecimento/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Macaca mulatta/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Fatores Etários , Envelhecimento/metabolismo , Animais , Betacoronavirus/fisiologia , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Inflamação/imunologia , Inflamação/veterinária , Inflamação/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta/virologia , Doenças dos Macacos/imunologia , Doenças dos Macacos/virologia , Pandemias/veterinária , Pneumonia Viral/veterinária , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/veterinária , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Carga Viral/imunologia , Carga Viral/veterinária , Replicação Viral/imunologia
18.
Gene ; 762: 145056, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32805313

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is a disease characterized by weakening arterial wall and permanent expansion with high mortality once rupture, which was involved with immune system activation. However, owing to technical difficulties, previous research has limited the impact of one or limited immune cells on AAA. METHODS: We analyzed the composition of immune cells using the CIBERSORT algorithm through transcriptome sequencing data from patients with stable (eAAA) and ruptured aneurysms (rAAA). The whole transcriptome sequencing data, including 17 patients with ruptured AAA and 31 patients with stable AAA were downloaded from Gene Expression Omnibus (GEO, GSE98278). After normalizing and data processing, five rAAA and seventeen eAAA patients entered the follow-up analysis. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to identify several pathways that were significantly enriched in rAAA compared to eAAA tissues. RESULTS: We demonstrated that the compositions of infiltrative immune cell in eAAA and rAAA were different. Naïve B cells, both resting and activated CD4+ memory T cells were found significantly higher in ruptured AAA, while memory B cells and activated mast cells were much less in ruptured AAA than that in stable AAA. Besides, PTX3 was significantly highly expressed in rAAA, which might be associated with the complement system and polarization of macrophages. Finally, differentially expressed genes and the related immune cells were mapped in a network to reveal the relationship between gene expression and infiltrative immune cells. CONCLUSION: We identified the infiltrated immune cell profile of eAAA and rAAA patients, which might be the potential target of AAA treatment.


Assuntos
Aneurisma da Aorta Abdominal/genética , Ruptura Aórtica/genética , Linfócitos B/metabolismo , Linfócitos T/metabolismo , Transcriptoma , Animais , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Células Dendríticas/metabolismo , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo
19.
Cardiovasc Pathol ; 49: 107261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32771878

RESUMO

Cardiac inflammation in Coxsackievirus B3 (CVB3)-induced myocarditis is a consequence of viral-related cardiac injury and immune response. Caspase-associated recruitment domain 9 (CARD9) is a critical adaptor protein involved in transduction of signals from various innate pattern recognition receptors. In this study, the role of CARD9 in acute viral myocarditis was evaluated. CARD9-/- and C57BL/6 mice were infected with CVB3. On day 7 postinfection, myocardial tissue and blood samples were collected and examined. After CARD9 knockout, mRNA and protein levels of transforming growth factor-ß(TGF-ß), interleukin-17A(IL-17A), and CARD domain of B-cell CLL/lymphoma 10(BCL-10) in the myocardium were markedly lower in CARD9-/- mice than in C57BL/6 mice with CVB3-induced viral myocarditis. This trend was similar for the pathological scores for inflammation and serum levels of cytokines interleukin-6(IL-6), interleukin-10(IL-10), interferon -γ(IFN-γ), TGF-ß, and IL-17A. These results suggest that the CARD9-mediated secretion of pro-inflammatory cytokines plays an important role in the immune response to acute viral myocarditis.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Infecções por Coxsackievirus/metabolismo , Enterovirus Humano B/imunologia , Miocardite/metabolismo , Miocárdio/metabolismo , Linfócitos T/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/genética , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocardite/genética , Miocardite/imunologia , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/patologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/virologia
20.
Lancet Haematol ; 7(9): e690-e696, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32791043

RESUMO

People living with HIV are a global population with increased cancer risk but their access to modern immunotherapies for cancer treatment has been limited by socioeconomic factors and inadequate research to support safety and efficacy in this population. These immunotherapies include immune checkpoint inhibitors and advances in cellular immunotherapy, particularly chimeric antigen receptor (CAR) T-cell therapy. Despite the field of cancer immunotherapy rapidly expanding with ongoing clinical trials, people with HIV are often excluded from such trials. In 2019, post-approval evaluation of anti-CD19 CAR T-cell therapy in people with HIV and aggressive B-cell lymphoma showed the feasibility of CAR T-cell therapy for cancer in this excluded group. Along with expanded treatment options for people with HIV is the ability to assess the effects of immunotherapy on the latent HIV reservoir, with certain immunotherapies showing the ability to alleviate this burden. This Series paper addresses the increased cancer burden in people with HIV, the increasing evidence for the safety and efficacy of immunotherapies in the context of HIV and cancer, and opportunities for novel applications of CAR-T therapy for the treatment of both haematological malignancies and HIV.


Assuntos
Infecções por HIV/patologia , Neoplasias Hematológicas/terapia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/transplante , Antígenos CD19/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Infecções por HIV/complicações , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/mortalidade , Humanos , Imunoterapia Adotiva , Taxa de Sobrevida , Linfócitos T/citologia , Linfócitos T/metabolismo
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